PROJECT SUMMARY ? This R01 proposal addresses a critical need in the advancing field of combination therapies involving potent alpha particle emitters. Radium-223 dichloride is an alpha particle emitting bone-seeking radionuclide range. In patients with bone metastatic castrate resistant prostate cancer (bmCRPC), which has a very poor prognosis, this therapy has achieved improved overall survival with a well-tolerated safety profile. There is great interest in further improving these treatment gains through combination with other therapies. However, there is a lack of basic science data to support which combinations may provide a significant benefit nor for which patients. This deficit has been brought into stark relief following unexpected negative outcomes in two combination trials. The need for a better understanding of how to combine alpha particle emitters with other therapies is significant beyond Radium-223 alone, as its approval has helped to generate considerable interest for other alpha particle emitting agents, many of which are entering clinical evaluation at this time. Here, we undertake multiple, independent investigations of means to improve drug delivery to disease sites, spare off-target tissues, and to more deeply understand the basis for positive and negative outcomes of combinations. This proposal is predicated on extensive preclinical investigation and emergent clinical findings and are tested in technically advanced models of disease that recapitulate key features of human bmCRPC. In Specific Aim 1 (S.A.1) we test the long term safety profile and anti-metastatic efficacy of combining 223Ra with an approved pharmacological modulator that improves drug delivery to the bone and reduces off-target uptake. S.A.2 extends our compelling pilot data into the molecular basis for the lethal combination of abiraterone acetate and 223Ra; the clinical evaluation of this combination was halted due to increased fracture and risk of death. In S.A.3 we investigate the impact of DNA repair defects on Radium-223 responses in controlled systems following intriguing findings in a limited patient cohort with improved responses to 223Ra. The impact of our findings will be immediate; our pilot data indicate molecular mechanisms to avoid toxicity, to predict those most likely to benefit from 223Ra, as well as identify combinations that may produce severe side effects. Long-term, these data and tools have considerable import in motivating improved management of the tens of thousands of patients with bone metastatic disease. The skills and knowledge of a multidisciplinary team of experts in the fields of nuclear medicine, radiation oncology, radiochemistry, preclinical disease models and pathology ensures the highest likelihood of achieving the proposed aims.